In the past year, Ozempic, Wegovy, Mounjaro and other weight loss drugs have made headlines and become household names in the United States. While the attention is recent, the science behind these drugs is not. They all belong to a class of peptidic molecules called glucagon-like peptide-1 (GLP-1) receptor agonists, which have been studied for more than two decades. These drugs mimic a natural peptide produced in the body called GLP-1, a molecule that plays a key role in regulating appetite and metabolism, but is degraded within minutes in the body by enzymes.
GLP-1 receptor agonists got their start in an unlikely place: the mouth of a lizard. A peptide that was discovered in Gila monster saliva, called exendin-4, was found to mimic the action of GLP-1 and was developed into the drug exenatide (sold under the name Byetta) for the treatment of type 2 diabetes. Exenatide (shown on the right, PDB 7LLL), which was the first GLP-1 receptor agonist approved by the FDA, shares just over 50% sequence identity with GLP-1, but has a similar structure and is able to activate the GLP-1 receptor, while avoiding rapid proteolytic degradation.
The GLP-1 receptor, which is a member of a large class of G protein-coupled receptors, undergoes a series of conformational changes when it is activated. In the absence of an agonist, the extracellular domain of the receptor is closed and interacts with the transmembrane domain (PDB 6LN2). On the intracellular side, the structure is tightly packed, stabilized by interactions between amino acids in different alpha helices. Upon binding GLP-1 (shown in pink on the right, PDB 6X18), the extracellular domain moves up to accommodate the ligand, which also causes an opening on the intracellular side of the receptor. This allows the binding and activation of a G protein (not shown), which in turn pushes one of the receptor’s transmembrane helices outward. The result is a disruption of stabilizing contacts within the receptor and the initiation of downstream signaling that influences appetite and metabolism.
Following the success of exenatide, scientists worked to refine GLP-1 receptor agonists to make them more stable, more effective, and more convenient to administer. One of the most successful products of this effort was semaglutide (PDB 7KI0), better known by its brand names Ozempic, Rybelsus, and Wegovy. Semaglutide includes substitutions and modifications that make it more resistant to proteolytic cleavage and that slow clearance from the body, allowing for once-weekly dosing (exenatide's original formulation, in contrast, required twice-daily injections).
Another major advance came with tirzepatide (PDB 7FIM), sold under the names Mounjaro and Zepbound. Tirzepatide is a dual agonist that activates both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, extending its effects beyond those of earlier drugs. It was designed by combining features of both GLP-1 and GIP, and produces very similar structural rearrangements in the activated GLP-1 receptor as the natural ligand.
Retatrutide (PDB 8YW3), a peptide-based drug that is not yet FDA-approved, is a triple agonist targeting the GLP-1 receptor, the GIP receptor, and the glucagon receptor. By including glucagon receptor activity, retatrutide not only suppresses appetite but has other impacts on metabolism. Clinical trials suggest that this combined mechanism produces greater weight loss than either semaglutide or tirzepatide. Structural studies show that retatrutide achieves triple agonism by maintaining highly conserved interactions across the three different receptors.
Despite the success of peptide-based GLP-1 receptor agonists, they come with significant shortcomings. Because peptides are broken down in the digestive tract, most of these drugs must be injected. An oral formulation of semaglutide, marketed as Rybelsus, can be used for the treatment of type 2 diabetes, but it has very low bioavailability, limited effects on weight loss, and is associated with significant side effects such as nausea. Peptide drugs also require refrigeration to prevent degradation and are more expensive to manufacture compared to small molecule drugs. These challenges fueled efforts to create non-peptide GLP-1 receptor agonists that could be taken orally. Discovering such molecules is difficult, however, as they must replicate the effects of large peptides that stabilize the active receptor through numerous and dispersed interactions. Even so, promising candidates have emerged.
One example is orforglipron (PDB 6XOX), a small molecule drug that binds to the GLP-1 receptor in a unique position high within the helical bundle of the receptor. Unlike peptide agonists, it interacts with a different set of receptor residues and yet still manages to activate the receptor. Studies have shown that the downstream signaling resulting from binding of orforglipron and GLP-1 are similar but distinct. Orforglipron is currently in Phase 3 clinical trials as a once-daily oral treatment for obesity, type 2 diabetes, obstructive sleep apnea, and hypertension.
Another candidate, danuglipron (PDB 6X1A), was designed to occupy the core of the receptor, overlapping with the position normally occupied by one end of GLP-1. Danuglipron binding stabilizes the receptor in a unique conformation that is dissimilar from those observed during GLP-1 or orforglipron binding. While early studies were encouraging, Pfizer discontinued the program in 2025 after cases emerged of drug-induced liver injury during clinical trials.
While peptide-based GLP-1 receptor agonists all bind to the GLP-1 receptor in similar ways, the small molecule orforglipron is much smaller with far fewer interactions. Click on the JSmol tab to take a closer look at how GLP-1 (PDB 6X18), semaglutide (PDB 7KI0), tirzepatide (PDB 7FIM), and orforglipron (PDB 6XOX) are able to stabilize the active form of the GLP-1 receptor, and compare these structures to that of the inactive GLP-1 receptor (PDB 6LN2).
